Gabapentin of formula (1), is the generic name of a well-known anticonvulsant agent, described for example in the Merck Index, 13th Edition (2001), page 767 (4342).

1-(aminomethyl)-1-cyclohexane acetic acid (Gabapentin) has been used for the treatment of cerebral disorders such as epilepsy, hypokinesia, faintness attacks and brain trauma. Commercially available gabapentin currently on the market is an anhydrous crystalline form that, hereinafter, will be referred to as form II. Several other gabapentin polymorphic forms have been described in the literature, being the more important gabapentin monohydrate (form I, EP0340677) and gabapentin form III (WO98/28255).
Many processes for the preparation of gabapentin have been hitherto described in the literature.
For example, WO99/18063 discloses a multi step synthesis wherein gabapentin of formula (1) is obtained as a final product after the catalytic hydrogenation of chemical intermediates comprising a cyano group. The involvement of cumbersome multi-step synthesis, high pressure hydrogenation and use of cyanides or other toxic reagents make these processes difficult from the technical point of view.
However, most of the reported synthesis proceed through the intermediate of an acid addition salt of gabapentin which is finally neutralized to gabapentin of formula (1).
This neutralization can be carried out with the use of ion exchange columns (U.S. Ser. No. 03/009,055, WO02/074727, U.S. Pat. Nos. 5,319,135, 5,693,845, 5,362,883, EP0432504, EP0414274, EP0414262, WO03/089403, WO02/034709, WO00/064857, U.S. Pat. No. 4,024,175, and EP0340677). In this neutralization process, solutions of acid addition salts of gabapentin in water or in short chain alcohols are eluted through ion exchange columns to get solutions of gabapentin of formula (1) in a free amino acid form. The rather long elution time needed, the large volumes of water or alcohols that should be evaporated and the need to introduce a rinse of the column in order to maintain the exchange capacity make these processes difficult to scale up.
In other cases, the neutralization can be carried out with the use of a base (WO98/28255, U.S. Pat. Nos. 5,362,883, and 53,191,385).
WO98/028255 discloses a process for preparing gabapentin of formula (1) consisting of dissolving gabapentin hydrochloride in a solvent and neutralizing it by addition of an amine in solution, said solvent being chosen in such a way that the amine hydrochloride formed during the neutralization is more soluble therein than the anhydrous gabapentin. In accordance with WO98/028255, a new form of anhydrous gabapentin, named form III, is prepared in the neutralization process. It is necessary to reprocess this form III by digestion or recrystallization in another solvent, to be able to prepare the pharmaceutical grade anhydrous gabapentin base, which is named form II in WO98/028255. This process does not require the use of ion exchange resins, but has the drawback that, unless closely adjusted amounts of neutralizing amine are used, the product obtained may be contaminated with appreciable amounts of the amine used in the neutralization and which have to be removed subsequently from the end product, by additional purification steps. Furthermore, this process also requires the preparation of an intermediate, the so-called form III, which has to be reprocessed, with the corresponding decrease in yield and productivity.
U.S. Pat. Nos. 5,362,883 and 5,319,135 disclose that gabapentin among other products, may be prepared from the acid addition salts thereof, e.g., from the hydrochloride, by their neutralization with a long list of bases, among which there are the free amines, sodium hydroxide, potassium hydroxide, calcium hydroxide and basic ion exchange resins. However, the examples (Method F) of said patents only describe the use of the said resins for neutralizing aqueous solutions of gabapentin hydrochloride, i.e. a method corresponding with the one already described for example in the aforementioned patent EP0340677. If sodium hydroxide, potassium hydroxide or calcium hydroxide are used as neutralizing agent, the obtained gabapentin is contaminated with mineral salts insoluble in organic solvents. The only way of getting rid of these mineral salts is by adding water, but then the yield decreases due to the high solubility of gabapentin in water. In addition, since water is used, the polymorph of gabapentin which is obtained is the monohydrate (Form I).
Finally, WO00/001660 discloses a process for the preparation of gabapentin in anhydrous form (i.e. form II), without using monohydrate gabapentin (i.e. form I), by treating an aqueous suspension of gabapentin with 2-methoxyethanol or 2-ethoxyethanol and crystallizing with an alcoholic solvent. In this process, the isolation of gabapentin monohydrate is avoided since water is eliminated by azeotropic distillation, however big volumes of water should be distilled in order to be removed.
There is, therefore, a need for developing alternative processes for the preparation of pharmaceutical grade gabapentin, allowing the industrial preparation of this product to be simplified and, therewith, the production costs to be reduced.